A group of 13 investigators in the Perelman School of Medicine at the University of Pennsylvania, which includes PI's on 26 different NIH grants, with over $6,700,000 grant support per year, requests funds for the purchase of a computational resource for structural biology and molecular biophysics. The resource is designed to leverage existing instrumentation and research groups working in the areas of Cryo-Electron microscopy (Cryo- EM), NMR, X-ray crystallography and scattering, single molecule biophysics, high resolution mass spectroscopy (MS), Hydrogen Exchange (HX) and macromolecular simulations. One function of the resource would be to support the Cryo-EM Tecnai G2 F20 TWIN 200kV field emission gun transmission electron microscope obtained with an earlier shared instrumentation grant. This instrument, part of a successful and well used EM core facility is now producing data at a rate that requires significantly higher throughput computer resources for 3D image reconstruction, in order to maximize return on the investment in Cryo-EM. The resource is targeted specifically for computationally intensive tasks which cannot be efficiently performed on the highly distributed, and already saturated computing facilities in the Perelman School of Medicine. The proposed hardware will make heavy use of state of the art graphics processing unit (GPU) hardware, which has been shown to provide unmatched performance per dollar on the type of computations required by structural biology and molecular biophysics. GPU-optimized software required for the most computationally intensive structural biology and molecular biophysics applications has already been developed, so the requested hardware could be put into use immediately. Major users have well-funded research programs that address important questions in diseases such as amyloidogenesis and neurodegenerative disorders, diseases of protein-misfolding, gene regulatory proteins and their aberrant regulation in cancer, defects in myosin leading to hypopigmentation and neurological disorders, identification and structural characterization of new protein targets for drugs and therapeutics. The requested computer resources will greatly advance these important biomedically relevant projects as well as those of other investigators using the Cryo-EM core.